Important roles for several microbial stress response systems in antibiotic resistance have been found. A. Independent regulation of antibiotic resistance gene by the marRAB (multiple antibiotic resistance) and soxRS (superoxide) stress response systems of Escherichia coli has been demonstrated. When the marRAB operon is transcriptionally activated due to exposure to certain antibiotics (chloramphenicol, tetracycline), aromatic weak acids (salicylate, 2,4-dinitrophenol) or mutations in the marR (repressor) gene, the marA product activates the transcription of a set of genes which helps the cells resist antibiotics and superoxides. The soxRS system which is activated by exposure to superoxide generating agents and nitric oxide also activates this set of genes by means of the SoxS transcriptional activator. The present work demonstrates that the two systems operate largely independently: deletion of marRAB does not prevent induction of soxRS by paraquat while deletion of soxRS does not prevent induction of marRAB by salicylate. In addition, the existence of a marRAB-independent pathway for induction of antibiotic resistance by salicylate has now been established. B. Escherichia coli and Salmonella typhimurium are resistant to >1 mg/ml concentrations of isoniazid (INH), a clinically important antituberculosis drug. The present work has shown that resistance is largely due to the function of peroxidases controlled by the OxyR peroxide response system. Mutants with defective oxyR (encoding the transcriptional regulator) or katG (encoding a hydroperoxidase) and ahp (encoding an alkyl hydroperoxide reductase) are susceptible to as little as 50 micro-g/ml of INH. The role of these genes appears to be to reduce the levels of peroxides within the cell. The addition of exogenous peroxides to resistant E. coli or Mycobacterium smegmatis increases their INH susceptibility while antioxidants reduces the susceptibility of sensitive cells. These results suggest that peroxides are needed to interact with INH to generate toxicity in both E. coli and M. smegmatis.